title: Clearance of the mutant androgen receptor in motoneuronal models of spinal and bulbar muscular atrophy.
abstract: Spinal and bulbar muscular atrophy (SBMA) is an X-linked motoneuron disease caused by an abnormal expansion of a tandem CAG repeat in exon 1 of the androgen receptor (AR) gene that results in an abnormally long polyglutamine tract (polyQ) in the AR protein. As a result, the mutant AR (ARpolyQ) misfolds, forming cytoplasmic and nuclear aggregates in the affected neurons. Neurotoxicity only appears to be associated with the formation of nuclear aggregates. Thus, improved ARpolyQ cytoplasmic clearance, which indirectly decreases ARpolyQ nuclear accumulation, has beneficial effects on affected motoneurons. In addition, increased ARpolyQ clearance contributes to maintenance of motoneuron proteostasis and viability, preventing the blockage of the proteasome and autophagy pathways that might play a role in the neuropathy in SBMA. The expression of heat shock protein B8 (HspB8), a member of the small heat shock protein family, is highly induced in surviving motoneurons of patients affected by motoneuron diseases, where it seems to participate in the stress response aimed at cell protection. We report here that HspB8 facilitates the autophagic removal of misfolded aggregating species of ARpolyQ. In addition, though HspB8 does not influence p62 and LC3 (two key autophagic molecules) expression, it does prevent p62 bodies formation, and restores the normal autophagic flux in these cells. Interestingly, trehalose, a well-known autophagy stimulator, induces HspB8 expression, suggesting that HspB8 might act as one of the molecular mediators of the proautophagic activity of trehalose. Collectively, these data support the hypothesis that treatments aimed at restoring a normal autophagic flux that result in the more efficient clearance of mutant ARpolyQ might produce beneficial effects in SBMA patients.
authors.affiliation: Sezione di Biomedicina e Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza sulle Malattie Neurodegenerative, Universita' degli Studi di Milano, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rusmini
authors.forename: Valeria
authors.initials: V
authors.lastname: Crippa
authors.forename: Elisa
authors.initials: E
authors.lastname: Giorgetti
authors.forename: Alessandra
authors.initials: A
authors.lastname: Boncoraglio
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cristofani
authors.forename: Serena
authors.initials: S
authors.lastname: Carra
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D050886:HSP20 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D018832:Molecular Chaperones; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013739:Testosterone / Q000494:pharmacology; D014199:Trehalose / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015853:Cysteine Proteinase Inhibitors; D050886:HSP20 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C490206:Hspb8 protein, mouse; D007976:Leupeptins; D018832:Molecular Chaperones; D009124:Muscle Proteins; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D049452:Green Fluorescent Proteins; D013739:Testosterone; C025946:3-methyladenine; D014199:Trehalose; D000225:Adenine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Androgen receptor; CAG repeat; Chaperones; HspB8; Motoneuron; Motoneuron disease; Neurodegeneration; Polyglutamine; Protein misfolding; Spinal and bulbar muscular atrophy